Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT6B

 Yu Sun., et al. Nat Med. 2012 Aug 5. doi: 10.1038/nm.2890

Speaker: Yu-Chi Su (蘇育琦)                                        Time: 14:10~15:00, Oct. 17, 20

Commentator: Dr. Cheng-Chan Lu (呂政展 老師)     Place: Room 601

Abstract:

Prostate cancer is one of the most common cancers affecting the male population. Although chemotherapy is the priority treatment of anti-cancer strategies, the resistance of tumors to cytotoxic therapeutics is a major impediment to more effective cancer treatment. These cytotoxicchemotherapeutic agents usually damage both tumor and benign cells. To prevent lethality in patients, high doses of most anticancer drugs are avoided. However, tumor cells might recover during therapeutic intervals and acquire drug resistance. In this study, the authors suggest that treatment-associated DNA damage responses in benign cells within the tumor microenvironment promote therapeutic resistance and subsequent tumor progression. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, they identified a spectrum of secreted proteins from the tumor microenvironment. Among these were Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). The authors showed that WNT16B promotes cancer cell proliferation and invasion by generating a prostate fibroblast cell line which expressed WNT16B or shRNA specific for WNT16B. Stable expression of WNT16B or conditioned medium from irradiated benign fibroblast enhanced cell proliferation. Wnt signaling is known to promote tumor invasion by inducing epithelial to mesenchymal transition (EMT). They further demonstrated that WNT16B signals through β-catenin and induces an EMT. In addition, the authors determined that genotoxic stress induces WNT16B expression through NF-ĸB, a stress-associated induction of inflammatory networks. Inhibition of β-catenin or NF-ĸB signaling attenuated protection of cancer cells from genotoxic stress. In conclusion, the authors indicate that damage responses in benign cells within the tumor microenvironment may directly contribute to enhancing tumor growth kinetics.

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